Project Summary This application outlines a training plan for a doctoral student to gain knowledge and research experience in human psychopharmacology (goal 1), psychophysiology (goal 2), reproductive neuroendocrinology (goal 3), advance statistical methods (goal 4), and science communication and professional skills (goal 5). The applicant wishes to become an independent researcher studying responses to psychoactive drugs. Through the proposed training plan, the applicant will acquire skills through didactic training, seminars, and hands-on research. She will become proficient in screening participants, selecting sensitive and reliable outcome measures, developing appropriate designs (goals 1, 2, & 3), and performing state-of-the-art statistical analyses. Professional goals will include acquiring familiarity with ethical issues, interpreting data (goal 4), and writing and speaking effectively (goal 5). She will meet regularly with her sponsor, co-sponsor, and consultants to advance her training in each of these domains. Her primary sponsor, Dr. Harriet de Wit, is an experienced substance abuse researcher, and her co-sponsor, Dr. Greg Norman, has expertise in psychophysiology and neuroendocrinology. In her project, the candidate will examine female-specific sources of variability in responses to oral THC, the primary psychoactive ingredient of cannabis. Females are increasingly using cannabis and are more susceptible to its adverse, stress-related, effects, such as tachycardia and anxiety. Yet, they remain underrepresented in preclinical and clinical cannabinoid research. Further, menstrual cycle-related variations in hormone levels, physiology, and basal mood may cause variation in acute drug response. This study will test the dose-dependent physiological and subjective effects of oral ?9-tetrahydrocannabinol (THC) vs placebo in healthy female occasional cannabis users at two phases of the menstrual cycle. Women will receive THC (7.5 or 15 mg) during either the early or late follicular phase of the cycle, in a double-blind and counterbalanced design. Estradiol levels will be measured at each session, and subjects will complete self- report subjective mood ratings during each session. The first aim is to compare subjective and physiological effects of THC during the early and late follicular phase of the menstrual cycle. The second aim is to determine whether circulating estradiol levels, independent of menstrual cycle phase, predict physiological and subjective response to acute THC. If there are differences in drug response between early and late follicular phase, a mediation analysis will determine whether circulating estradiol levels mediate these differences. The final aim is to determine other moderators of subjective response to THC. The rationale for the project is to better understand the risks of cannabis use, to maximize medical potential and minimize public health risks. The expected outcome of this work is to understand how circulating estradiol levels affect physiological or subjective response to THC. Uncovering the individual differences in response to THC will allow for more preventive action against cannabis-induced anxiety, paranoia, and psychosis.